Acquired resistance to apoptosis is one of the hallmarks of malignancy. As apoptosis can be induced through multiple pathways, tumor cells circumvent apoptosis by a variety of mechanisms. A novel mechanism of apoptotic resistance in tumorigenesis is proposed based on correlated expression of a hi-directional gene SPAF (spermatogenesis associated factor) and AS-FGF-2 (anti-sense fibroblast growth factor-2), which are regulated from a shared promoter. We initially identified SPAF as a novel AAA (ATPase associated with diverse activities)-protein family member specific to early spermatogenesis and malignant conversion of mouse epidermal keratinocytes. Ectopic expression of SPAF was detected in multiple human cancers (8 in 11 specimens tested). Analysis of SPAF expression in spermatogenesis revealed that SPAF is specifically expressed in spermatogonia (male germ stem cells) at early stages but distinctly absent in spermatogonia undergoing apoptosis. Correlated expression of AS-FGF-2 and SPAF was found in normal testis and malignant cells in the epidermal carcinogenesis model. Both SPAF and AS-FGF-2 are localized in mitochondria. Given that SPAF likely functions as a membrane fusion protein and AS-FGF-2 belongs to the MutT family generally involved in the hydrolysis of oxidized nucleoside diphosphate-containing substances, we hypothesize that SPAF and AS-FGF-2 cooperatively protect cells against apoptosis by maintaining mitochondrial membrane stability (SPAF) and alleviating oxidative stress in mitochondria (AS-FGF-2). Activated expression of SPAF and AS-FGF-2 could be a survival mechanism to evade apoptosis in malignant tumor cells as well as germ stern cells. This hypothesis will be tested by: 1) evaluating their effects in preventing mitochondrial permeablization (SPAF) and relieving oxidative stress (AS-FGF-2) in response to apoptotic stimuli; 2) characterizing their molecular mechanisms by identifying SPAF-associated proteins and substrates of AS-FGF-2; 3) investigating their oncogenic roles in tumorigenesis; 4) Establishing the relevance of SPAF as a malignant marker for diagnosis and prognosis in human skin and head & neck cancers. The characterization of this bi-directional gene may provide useful prognosis markers as well as new targets for cancer therapy.